Oncolytic viruses (OV) are novel replicating therapeutics selected or designed to preferentially grow in and kill cancer cells. Diverse OV platforms have shown promise for the treatment of several types of cancers (1-5). Due to the self-replicating nature of OVs, the principle challenge in OV therapy is not initial saturation of all the tumors but rather efficient spreading within tumor cells upon infection of a reasonable amount of cancerous tissue. Much like most live vaccines, essentially all OVs have been genetically modified or selected for attenuated growth. While this limits the spread of OVs in normal host tissues, it can also blunt their natural ability to rapidly spread within and between tumors (6).
Vesicular stomatitis virus (VSV) is an OV that has shown outstanding efficacy in several in vivo cancer models (2, 3, 7). VSV is a small, enveloped, negative strand RNA rhabdovirus that is particularly sensitive to type I Interferons (IFN), a key component of normal innate cellular anti-viral immunity. In most cancers, IFN response pathways are defective and VSV can be extremely effective (2, 3). However, several cancers retain robust anti-viral defenses, rendering VSV much less effective when used alone (5, 8).
We have previously shown that histone deacetylase inhibitors (HDI) enhance the ability of VSV to infect and kill resistant tumor cells due in part to HDI-induced dampening of IFN mediated anti-viral response (9) and to enhanced apoptosis (10). Continual administration of HDIs prior to and following VSV administration in mice led to better spread of the virus preferentially within tumors and led to reduced tumor growth in the combination treatment as opposed to either treatment alone. Because continuous administration of HDIs can lead to various toxicities including cardiac toxicity in humans, it is desirable to identify other small molecules that could be used to enhance OV efficacy.
There is a need in the art to identify compounds and compositions that enhance virus growth, spread or cytotoxicity. There is also a need in the art to identify compounds and compositions that enhance oncolytic virus efficacy. Further, there is a need in the art to identify novel methods for treating cancer cells in vitro and in vivo.